A combination of phase transfer catalyst and ultrasonic irradiation promotes synthesis of mandelic acid

Article abstract of DOI:10.14233/ajchem.2014.15441

A combination of phase transfer catalyst and ultrasonic irradiation used to promotes synthesis of mandelic acid from benzaldehyde with chloroform. The main advantages of this method are that the reaction time is much shorter and the yield is higher than t

Full text of DOI:10.14233/ajchem.2014.15441

Asian Journal of Chemistry; Vol. 26, No. 2 (2014), 455-457
http://dx.doi.org/10.14233/ajchem.2014.15441
A Combination of Phase Transfer Catalyst and Ultrasonic
Irradiation Promotes Synthesis of Mandelic Acid
*
YU-QUAN ZHANG , XU-DONG ZHENG, KE GAI, YAN-CHUN LI and DONG-PING CHENG
College of Chemistry and Chemical Engineering, Longdong University, Lanzhou Road 54 Xifeng, Qingyang 745000, P.R. China
*Corresponding author: E-mail: zhyq118@sohu.com
Received: 7 March 2013;
Accepted: 22 July 2013;
Published online: 15 January 2014;
AJC-14564
A combination of phase transfer catalyst and ultrasonic irradiation used to promotes synthesis of mandelic acid from benzaldehyde with
chloroform. The main advantages of this method are that the reaction time is much shorter and the yield is higher than those of the
classical method. p-Methoxymandelic acid was also obtained in 58 % yield under the same reaction conditions.
Keywords: Tetrabutyl ammonium bromide, Mandelic acid, Ultrasonic activation, Phase transfer catalysis.
Mandelic acid (3a): Yield: 83 %; white solid, m.p. 118-
119 ºC; 1H NMR (300 MHz, CDCl3), δH 7.25(5 H, m), δH 5.10
(1H, s), δH 4.70 (2H, s); EI-MS m/z151.9 (M+).
INTRODUCTION
The mandelic acid, i.e., α-hydroxyphenylacetic acid is a
racemate and usually an important starting material for
resolution to obtain (R)-mandelic acid and (S)-mandelic acid
1. (R)-Mandelic acid is mainly used as a key intermediate for
the production of semisynthetic cephalosporins and penicillins
and also for the synthesis of other pharmaceuticals such as
antitumour and antiobesity agents. Therefore, many approaches
for the production of mandelic acid have been reported, but
they usually require long reaction time and the yield was very
low2.
p-Methoxymandelic acid (3b): Yield: 58 %; white solid,
110-113 ºC; 1H NMR (400 MHz, CDCl3), δH 3.80 (3H, s), δH
5.20 (1H, s), δH 6.89(2H, d, J = 8.8 Hz), δH 7.34 (2H, d, J = 8.4
Hz); EI-MS m/z 182 (M+).
EXPERIMENTAL
All the reagents employed in the synthesis were of
analytical reagent grade. The materials were used as purchased
and CHCl3 was used directly without any additional purifi-
cation. Melting points were uncorrected. FT-IR spectra were
recorded on a Thermo Nicolet 67 FT-IR spectrophotometer
with 4 cm-1 resolution. All NMR analyses were performed on
a Bruker spectrometer (300 or 400 MHz) in CDCl3; TMS (1H
NMR) was used as internal standards. Respectively, Sonication
was performed in Shanghai SK-250LH ultrasonic cleaner with
the frequency of 59 kHz.
Sonication also increases the reaction rate and avoids the
use of high reaction temperatures3. Numbers of organic reactions
have been revisited by means of ultrasonic waves4-6. Compared
with traditional methods this technique is more convenient
and easily controlled and is more appropriate in the considera-
tion of green chemistry concepts7.
In this context, our attention was focused on the fact that
phase transfer catalyst and ultrasonic irradiation could be a
successful way to synthesize mandelic acid. This method is
benefits from the rate enhancement effects found when using
ultrasonic irradiation and phase transfer catalyst. Herein, we
propose to present our studies toward the ultrasound-assisted
synthesis of mandelic acid catalyzed by phase transfer catalyst
tetrabutyl ammonium bromide (TBAB) (Scheme-I).
General procedure:To the mixture of the distilled benzal-
dehyde (1a, 96 mmol), tetrabutyl ammonium bromide (TBAB,
3 mmol) and CHCl3 (2.240 mmol) in100 mL three-neck
rockered flask at 55-60 ºC under N2, 50 % aq. NaOH (30 mL)
was added dropwise in 1 h under ultrasonic irradiation, After
adding, the above mixture continued to react at 55-60 ºC for
2 h under ultrasonic irradiation. Water (20 mL) was then added
to the mixture, which was extracted by Et2O (2 × 10 mL). The
water phase was separated, collected, acidified the pH value
to 1-2 by 50 % aq. H2SO4 and extracted by Et2O (2 × 10 mL).
Subsequently, the organic phase was combined, dried over
OH
50% aq NaOH/TBAB
CHO
+
CHCl
3
R
R
55-60 °C, 2 h,U.S
COOH
Scheme-I

456 Zhang et al.
Asian J. Chem.
anhydrous Na2SO4, concentrated in vacuo and purified by
recrystallization in toluene to give 3a, which was characterized
by 1H NMR, EI-MS and m.p.
of TBAB was too less, the reaction rate would be decreased
and the corresponding yield of 3a was reduced (entries 7, 14-
16). Moreover, the influences of the reaction temperature
(ultrasonic radiation frequencies, base and time on the reaction
yields were also studied and the best result was achieved when
the reaction temperature was at 55-60 ºC and the reaction time
was 2 h (83 %, entry 7), respectively. It was obvious that the
best yield of 3a could not be obtained even if the reaction
time prolonged to 3 h (75 %, entry 20) and the reaction tempe-
rature was raised to 70-80 ºC (54 %, entry 10).
RESULTS AND DISCUSSION
The effects of ultrasound wave, tetrabutyl ammonium
bromide, reaction time, ultrasonic radiation frequencies, base,
reaction way and temperature on the reaction were investigated
as summarized in Table-1.
As shown in Table-1, in the absence of ultrasound, when
benzaldehyde (1a, 96 mmol), CHCl3 (2.240 mmol) and
tetrabutyl ammonium bromide (3 mmol) was reacted for 2 h
at 55-60 ºC after adding 50 % aq. NaOH (30 mL), mandelic
acid (3a) was obtained in a 52 % yield (entry 18); while under
ultrasonic irradiation, 3a was obtained in a 83 % yield (entry
7). Therefore, it was clear that the ultrasound could accelerate
the synthesis of mandelic acid.We then studied the reaction
conditions under ultrasound. When TBAB was added to the
above reaction mixture used as phase transfer catalyst under
ultrasonic irradiation for 2 h at 55-60 ºC, the yield of 3a was
increase from 35 to 83 % (entries 14 vs. 7), which encouraged
us to observe the influence of the amount of TBAB on the
reaction yields (entries 8, 14-16). It was found that the best
yield of 3a was obtained when 3 mmol of TBAB was used as
phase transfer catalyst. The possible reason was: TBAB could
be collapsed to form a cavity, for example, the inner and the
external parts of which have the lipophilic and the hydrophilic
properties, respectively. When TBAB was used as phase transfer
catalyst, the benzaldehyde entered into the inner part of a cavity
of the TBAB, while the corresponding external part was used
to incorporate the TBAB from CHCl3. Consequently, the
benzaldehyde was easily to approach the trichloromethyl
anion to complete the reaction (83 %, entry 7). If the amount
The effect of various base used in the formation of 3a
was studied and NaOH was found to be the best base for the
reaction when NaOH was used as base, the yield of 3a was 83
%, whereas the yield is 79 and 0 % respective when reaction
use KOH or K2CO3 as base (entry 18, 19). The best result was
achieved when the ultrasonic radiation frequencies was at
59 kHz and the reaction time was 2 h (83 %, entry 7), whereas
the yield is 63 % when the ultrasonic radiation frequencies
was at 43 kHz (entry 21).
Finally, adding way was studied, when the mixture of
benzaldehyde, TBAB and CHCl3 in100 mL three-neck rockered
flask at 55-60 ºC, 50 % aq. NaOH was added dropwise in 1 h
under ultrasonic irradiation, then continues to react 2 h and to
give the good yield (83 %, entry 7), whereas the yield is only
53 % using one-pot reaction (entry 22).
Evidently, of the ultrasound wave, TBAB, reaction time,
ultrasonic radiation frequencies, base and temperature
screened, the best yield of 3a (83 %) was obtained when the
molar ratio of benzaldehyde/CHCl3 /TBAB/was 96/240/3/ and
the reaction was proceeded 55-60 ºC for 2 h under ultrasonic
irradiation . In additionally, p-methoxymandelic acid (3b) was
also prepared in a 58 % yield by using the above same reaction
conditions (Scheme-I).
TABLE-1
SYNTHESIS OF 3a UNDER SONICATION
Temperature
(ºC)
Ultrasonic radiation
frequencies
Amount of
TBAB (mmol)
Adding time
(h)
Reaction time
(h)
Isolated yields
(%)
Entry
Base
1
2
35-40
40-45
45-50
50-55
55-60
55-60
55-60
60-65
65-70
70-80
55-60
55-60
55-60
55-60
55-60
55-60
55-60
55-60
55-60
55-60
55-60
55-60
59
59
59
59
59
59
59
59
59
59
59
59
0
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
3
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0.5
0.5
0.5
1.0
1.0
1.5
2.0
2.0
2.0
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
3.0
2.0
3.0
37
35
42
53
58
62
83
72
66
54
51
53
26
35
59
78
52
79
0
3
3
4
3
5
3
6
3
7
3
8
3
9
3
10
11a
12a
13c
14
15
16
17
18
19
20
21
22
3
3
3
3
59
59
59
0
0
2
2.5
2
59
59
59
43
59
2
Na2CO3
NaOH
NaOH
NaOH
2
3
75
63
53
3
3
aOne-pot reaction, bReaction time, cStirred without sonication and TBAB.

Vol. 26, No. 2 (2014)
Phase Transfer Catalyst and Ultrasonic Irradiation Promotes Synthesis of Mandelic Acid 457
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Y.M. Ding, Jiangsu Chem. Ind., 32, 31 (2004); (c) F.Z. Han, B. Wang,
Conclusion
In summary, we have found an efficient and practical
procedure for the preparation of mandelic acid and p-methoxy-
mandelic acid by using tetrabutyl ammonium bromide as phase
transfer catalyst under ultrasonic irradiation.
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ACKNOWLEDGEMENTS
The authors thank Scientific and Research Projects of
Department of Education of Gansu Province for 2012 and the
Longdong University Science Technology Development Foun-
dation (XYZK0504) for financial support.
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14, 213 (2007).
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